Investigating the role of lectins in LAG3 function and T cell activity
| dc.contributor.author | Mohideen, Shifa Fatima | |
| dc.contributor.examiningcommittee | Murooka, Thomas (Immunology) | |
| dc.contributor.examiningcommittee | Yao, Xiao-jian (Medical Microbiology and Infectious Diseases) | |
| dc.contributor.guestmembers | N/A | |
| dc.contributor.supervisor | Fowke, Keith | |
| dc.date.accessioned | 2024-04-01T18:18:40Z | |
| dc.date.available | 2024-04-01T18:18:40Z | |
| dc.date.issued | 2024-03-27 | |
| dc.date.submitted | 2024-03-22T21:12:25Z | en_US |
| dc.date.submitted | 2024-03-27T06:04:43Z | en_US |
| dc.degree.discipline | Medical Microbiology and Infectious Diseases | |
| dc.degree.level | Master of Science (M.Sc.) | |
| dc.description.abstract | During prolonged antigen exposure, as in cancer or HIV, surface inhibitory receptors called immune checkpoints (ICs), like Lymphocyte Activation Gene-3 (LAG3) are upregulated on T cells to provoke immunosuppression and evade immune control. Despite well-characterized LAG3-induced T cell exhaustion inhibiting cell function and cytokine responses, much about LAG3 remains elusive. LAG3’s extensive N-glycosylation, constitutes a recognition interface for LAG3-expressing cells to communicate and engage with binding partners in their microenvironment. Accordingly, its N-glycosylated residues can coordinate immune interactions and IC function by potentially engaging glycan-binding proteins or lectins such as Galectin-3 or LSECtin, often secreted in these disease contexts. However, the precise mechanisms of this interaction and its functional consequences on LAG3-mediated T cell activity remain a significant knowledge gap. This thesis clarifies that LSECtin and Galectin-3 exhibit dose-dependent specificity for binding LAG3 N-glycans through their carbohydrate recognition domains, affirming the necessity of N-glycosylation in LAG3-lectin engagements. As an additional immune regulatory layer, this study also resolves that Galectin-3 and LSECtin binding augments LAG3-mediated T cell suppression, with LSECtin yielding stronger inhibitory effects. Contingent on LAG3, these lectin-driven reductions in pro-inflammatory cytokines, IL-2 and IFNγ, may skew and compromise antiviral and antitumor immunity. Conversely, this lectin-induced T cell inhibition is alleviated with N-glycan removal. Addressing a critical research gap in LAG3 literature, this dissertation uncovers a previously underappreciated mechanism of how post-translational N-glycosylation and lectins modulate and instruct LAG3-mediated T cell suppression. In broadening the scope of LAG3 biology, such insights can spur further research into the complex molecular interplays engendering immune exhaustion and immune escape to better relieve disease progression. By illuminating promising therapeutic targets regarding LAG3-lectin engagements, the research herein can optimize and inform the efficacy of a lectin or LAG3 blockade clinically. Targeted interventions of this nature, alongside current immunotherapies, can refine current cure strategies in addressing undesired immune dysfunction and reinvigorating host immunity for better patient prognosis. | |
| dc.description.note | May 2024 | |
| dc.identifier.uri | http://hdl.handle.net/1993/38126 | |
| dc.language.iso | eng | |
| dc.rights | open access | en_US |
| dc.subject | LAG3 | |
| dc.subject | immune exhaustion | |
| dc.subject | lectins | |
| dc.subject | T cell exhaustion | |
| dc.subject | immune checkpoints | |
| dc.subject | glycosylation | |
| dc.subject | immune modulation | |
| dc.title | Investigating the role of lectins in LAG3 function and T cell activity | |
| dc.type | master thesis | en_US |
| local.subject.manitoba | no | |
| oaire.awardTitle | CIHR - Canadian Graduate Scholarships Masters (CGSM) | |
| oaire.awardURI | https://www.nserc-crsng.gc.ca/Students-Etudiants/PG-CS/CGSM-BESCM_eng.asp | |
| project.funder.identifier | https://doi.org/10.13039/501100000024 | |
| project.funder.name | Canadian Institutes of Health Research |